Background: Percutaneous ablation of neoplastic tissue by radiofrequency ablation (RFA), microwave ablation (MWA) or brachytherapy is considered a potentially curative treatment for early HCC, but recurrence rates are high. Local ablative therapies release immunogenic stimuli that can trigger an anti-tumoral immune response, which is, however, dampened by counter-regulatory mechanisms mediated through immune checkpoints, such as CTLA-4 and PD-1. Combining local therapies with immunotherapies may shift the balance to a more robust immunostimulatory response. We therefore hypothesized that peri-interventional treatment with pembrolizumab may synergize with and improve outcome of local ablative therapy. Methods: This single arm phase II trial investigates peri-interventional treatment with pembrolizumab combined with RFA/MWA or brachytherapy, or - as recommended for tumors larger than 3 cm – combined with TACE and RFA/MWA or brachytherapy in early-stage HCC with maintained liver function (Child Pugh A) who did not receive prior local or systemic therapy. Pembrolizumab (200mg, q3w) was administered intravenously for 2 cycles, followed by radiologic imaging and local therapy. Pembrolizumab was continued for up to 12 months. The primary efficacy endpoint was defined as overall response rate (ORR, RECIST 1.1) after 2 cycles of pembrolizumab and before local therapy while secondary endpoints are time to recurrence (TTR, defined as the length of time after performance of local ablation resulting in confirmed absence of viable tumor tissue until documented tumor recurrence), recurrence free survival and overall survival (OS) along with safety and tolerability. Results: 30 patients (pts, ECOG 0 or 1) were enrolled in 9 centers in Germany, with a median age of 70 years and a predominance of male pts (73.3%). All pts received at least 1 dose of study treatment and the median number of cycles was 13. ORR was 13.3%, with 6.7% complete responses (CR) and 6.7% partial responses (PR) after two cycles of pembrolizumab and before local ablation. Subsequent local ablation was performed in 25/30 pts. With ongoing follow-up median of 14 months (Sep 2022), provisional median overall survival time (mOS) was not reached and provisional median time to recurrence (TTR) was 17.41 months. No new safety signs were observed. Conclusions: The study did not meet its primary endpoint. The hypothesized ORR of 30% before local therapy was not reached. However, there is evidence for the efficacy of peri-interventional treatment with pembrolizumab combined with local ablative therapy without new safety signals. Our findings support further evaluation of this combination treatment in early-stage HCC. Clinical trial information: NCT03753659.